Method of mitigating adverse drug events using omega-3 fatty acids as a parenteral therapeutic drug vehicle

ABSTRACT

A method of parenterally administering a composition, the method including parenterally administering to a person a composition including at least one omega-3 fatty acid and at least one drug, wherein the at least one omega-3 fatty acid source and the at least one drug are administered simultaneously.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority and is acontinuation-in-part of U.S. application Ser. No. 12/923,257 filed onSep. 10, 2010, the entire contents of which are incorporated byreference. U.S. application Ser. No. 12/923,257 claims the benefit ofpriority and is a continuation-in-part of U.S. application Ser. No.12/382,196 filed on Mar. 11, 2009, and is a continuation-in-part ofInternational Application No. PCT/US2010/000723 filed on Mar. 11, 2010,which in turn is a continuation-in-part of U.S. application Ser. No.12/382,196 filed on Mar. 11, 2009, the entire contents of both of whichare incorporated by reference herein.

BACKGROUND

1. Field

The present disclosure relates to medicinal formulations that can, forexample, contain sufficient amounts of parenteral omega-3 fatty acidsderived from naturally-occurring marine oils, and that can function as anovel “therapeutic” drug carrier, or vehicle. This proposed novelapplication is in contrast to conventional “pharmaceutical” drugcarriers, or vehicles.

The marine oil-containing formulations can be in the form of an emulsiondrug vehicle, comprising omega-3 fatty acids, attached to triglycerideor ester molecules, as an oil component of the emulsion, in addition toa water component. These two components of the emulsion, with the aid ofa suitable surfactant, can exist as separate, but miscible phases, alongwith one or more drugs that, when parenterally administered withoutaccompanying omega-3 fatty acids-containing marine oil, would often beexpected to cause collateral damage to a vital organ. The novel marineoil-containing formulation can be given by intravenous administration,as an oil-in-water emulsion containing the drug(s). The addition of theomega-3 fatty acids (for example, eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA) and/or docosapentaenoic acid (DPA)) toformulations containing selected drugs can reduce at least one adverseevent profile of those drugs upon intravenous administration. The atleast one adverse event profile can result from a drug toxicity, and canbe manifested by oxidative stress, inflammation, immune stimulation orischemia of one or more vital organs, or a combination thereof.

2. Related Art

Bioactive omega-3, or n3, fatty acids (n3-FAs) are present innaturally-occurring marine oil triglycerides and are contained in avariety of commercial products as nutritional supplements, in suchforms, for example, as soft gelatin capsules, foods, enteral nutritionformulations, and parenteral oil-in-water nutrition emulsions. As well,semi-synthetically-derived n3-FAs also exist in a highly purified form,such as omega-3 acid ethyl esters in liquid-filled capsules, used forthe treatment of hypertriglyceridemia. The bioactive components ofmarine oils can consist of three main omega-3 fatty acids: namely,eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and, to a lesserextent, docosapentaenoic acid (DPA).

In the critical care setting, the administration of clinical nutritionsupplemented with omega-3 fatty acids in fish oil-containing lipidinjectable emulsions has been shown to reduce mortality, the use ofantibiotics and the length of hospital stay (Reference [8] and [17]).These general beneficial effects were observed in acutely ill surgicalpatients, but the specific reasons for these positive findings were notclear, as noted by the following excerpt from one of the studyconclusions: “In view of the lack of substantial study literatureconcerning diagnosis-related nutritional single-substrate interventionin the critically ill, the present data can be used in formulatinghypotheses . . . .” (Reference [8]). In other words, there is evidenceto support the general, or nonspecific, clinical benefits of providingn3-FAs to acutely ill patients, but the reasons for these benefits arepoorly understood.

By comparison, in critically ill medical patients, supplementation withfish oil parenteral nutrition emulsions did not affect inflammation oroutcome (Reference [33]). Finally, in a recent review about the role offish oil-containing parenteral nutrition emulsions, the followingstatement summarizes their present status in clinical medicine: “ . . .the influence on inflammatory processes, immune function and clinicalendpoints is not clear, since there are too few studies and those thatare available report contradictory findings” (Reference [31]). Due tothe heterogeneity of patient populations, and the complex array ofdiseases and treatments, present application of n3-FAs as such, isnon-specific. Moreover, there are significant qualitative differenceswith respect to available fish oil emulsions and various oilcompositions (U.S. application Ser. No. 12/382,196 and InternationalApplication No. PCT/US2010/000723), further masking any potentialclinical benefits.

SUMMARY

A embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising at least one omega-3 fatty acidand at least one drug.

A further embodiment is a pharmaceutical composition for parenteraladministration comprising

a) an omega-3-fatty acid component selected from the group consisting ofomega-3-fatty acid triglycerides and/or omega-3-fatty acid ester, suchas omega-3 fatty acid ethyl ester; and

b) at least one drug.

Preferably, the parenteral administration of the composition of theinvention is an intravenous administration.

An exemplary embodiment can address a significant aspect in thetreatment of acutely ill patients requiring intravenous support, namelydrug therapy, which can be a significant contributor to determiningclinical outcome. Intravenous therapies can be prescribed in varioussettings (for example, hospital, ambulatory care, hospice, nursing home,rehabilitation or home) depending upon the patient, the disease and theprognosis. The co-administration of a parenteral drug known to causedamage to vital organs, but now accompanied by specific n3-FAs as atherapeutic drug vehicle, at the onset of medication therapy, can allowrapid incorporation of n3-FAs into plasma cell membranes. The n3-FAs canreplace n6-FAs present from typical dietary sources, and therefore theformer can reduce injury to these vital organs, for example, by alteringthe production of lipid mediators produced, and, likely improvingclinical outcomes.

According to an exemplary aspect, a method of parenterally administeringa composition is provided, the method comprising parenterallyadministering to a person a composition comprising at least one omega-3fatty acid and at least one drug, wherein the at least one omega-3 fattyacid and the at least one drug are administered simultaneously.

Therefore, according to a preferred embodiment of the pharmaceuticalcomposition the at least one omega-3 fatty acid and the at least onedrug are administered simultaneously. In one embodiment of the presentinvention the pharmaceutical composition can also be consisting of apharmaceutical system wherein the individual components of thecomposition are partly or completely separated from each other. Thepharmaceutical system can have two or more compartments. A furtherembodiment of the invention is a pharmaceutical system for parenteraladministration comprising at least two compartments

a) the first compartment comprising an omega-3-fatty acid componentselected from the group consisting of omega-3-fatty acid triglyceridesand omega-3-fatty acid ester, such as omega-3 fatty acid ethyl ester;and

b) the second compartment comprising at least one drug,

wherein said omega-3-fatty acid component and said drug are administeredsimultaneously. In an exemplary embodiment prior to the administrationof the components present in the compartments of the pharmaceuticalsystem a mixing step is conducted wherein the content of the firstcompartment is combined with the content of the second compartment.Alternatively, the content of the first container and the content of thesecond container can be administered to the patient individually butsimultaneously. According to a preferred embodiment the content of thefirst compartment is administered intravenously while at the same timethe content of the second compartment is administered, preferablyadministered intravenously. Preferably, the first compartment comprisesthe omega-3-fatty acid component as a oil in water emulsion and thesecond compartment comprises a drug dissolved in a liquid, preferablywater. For hospitals and in case of emergencies a kit comprising thedifferent components of the pharmaceutical composition of the inventioncan be helpful. A further embodiment of the present invention is a kitcomprising

a) one or more sterile container(s) comprising an omega-3-fatty acidcomponent selected from the group consisting of omega-3-fatty acidtriglycerides and omega-3-fatty acid ester, such as omega-3 fatty acidethyl ester; and

b) one or more sterile container(s) comprising at least one drug.

Prior to the administration to the patient the content of the differentsterile containers of the kit of the invention can be mixed to form thepharmaceutical composition of the invention. Alternatively, the contentof the different sterile container(s) can be administered to the patientseparately but simultaneously.

According to an exemplary aspect, a composition can contain bioavailableamounts of naturally- or synthetically-derived omega-3 fatty acids(i.e., n3-fatty acids, or n3-FAs). The omega-3 fatty acids can bepresent in a sufficient concentration as a pharmaceutical product inorder to provide a therapeutic benefit, along with a prescribed drugwhose side effect profile is associated with significant damage to vitalorgans. This combination can form a unique “therapeutic drug vehicle”,or “TDV” (U.S. application Ser. No. 12/382,196 and InternationalApplication No. PCT/US2010/000723).

According to another exemplary aspect, a composition containing both atleast one prescribed drug and n3-FA-containing oil, as an oil-containinginjectable emulsion, is administered by an intravenous route ofadministration.

According to another exemplary aspect, a combined intravenousadministration of concentrated n3-FAs and at least one prescribed drugknown to cause collateral damage to vital organs in a single injectableformulation can ensure the highest bioavailability and rapidincorporation of n3-FAs into plasma membranes not achievable by the oralor enteral routes of administration.

According to another exemplary aspect, at least one adverse consequenceof drug toxicity to vital organs can be ameliorated or eliminated by thepharmacological actions of the n3-FAs, EPA, DHA and/or DPA, which canact to reduce organ injury from pronounced oxidative stress,inflammation, immune modulation, and/or ischemia affecting one or morevital organs.

According to another exemplary aspect, amounts of bioactive n3-FAs,i.e., the sum of EPA, DHA and/or DPA, ranging in total concentrationfrom 1 to 300 mg/kg, are present in a parenteral formulation in order tomitigate damage to one or more vital organs caused by the at least oneprescribed drug that is/are also present in the composition.

According to another exemplary aspect, the type(s) and relative amountsof bioactive n3-FAs present in the formulation can vary from 0 to 100%for each n3-FA oil component, for example, EPA, DHA and DPA, for a giventotal concentration of all n3-FA oil components.

According to another exemplary aspect, the effective combination(EPA±DHA±DPA) and dose of n3-FAs (1 mg/kg to 300 mg/kg), along with eachprescribed drug in the injectable formulation can be n3FA+drug-specific,n3-FA+drug category-specific, or apply to a broad spectrum of drugs thatrespond to a specific combination-dose n3-FA regimen.

According to another exemplary aspect, the prescribed drug can reside ineither the oil fraction or the water fraction of the injectableformulation, i.e., within the “dispersed” (i.e., “internal”) or“continuous” (i.e., “external”) phase of an emulsion, depending onwhether the drug is oil-soluble or water-soluble, respectively.Accordingly, the lack of pharmaceutical consequence of the location ofthe drug, i.e., whether it resides in the dispersed or continuous phase,is novel in this disclosure. That is, the drug in most traditionaldrug-based injectable emulsions is usually water-insoluble, andtherefore it necessarily almost always resides in the dispersed (oil)phase. Consequently, such emulsions primarily serve only as drugcarriers, or pharmaceutical drug vehicles. In contrast, in the presentdisclosure, the n3-FA oil-containing “carrier” itself can play an activepharmacological role as a therapeutic drug vehicle, independent ofwhether the drug resides in the oil or water fraction of the emulsion,for example, regardless of whether it is located in the internal(dispersed) or external (continuous) phase of the emulsion.

According to another exemplary aspect, the n3-FAs combined with aparticular drug can accentuate the pharmacological actions of theintended drug therapy, independent of the role of the n3-FAs in reducingthe damage to organs caused by the particular drug alone. Thus,improvement in the therapeutic response of the drug therapy can improvethe clinical outcome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the cytotoxic effects of 24 h treatment with Ketorolac atvarious concentrations on mouse intraglomerular mesangial cells (SV40MES 13), according to an exemplary aspect.

FIGS. 2A to 2C show the effects of 48 h treatment with 0.005%concentrations of LO-3 5/5 (FIG. 2A), LO-3 7/3 (FIG. 2B) and LO-3 9/1(FIG. 2C) on cytotoxic effect of Ketorolac in mouse intraglomerularmesangial cells (SV40 MES 13), according to an exemplary aspect.

FIGS. 3A to 3C show the effects of 48 h treatment with 0.01concentration of LO-3 5/5 (FIG. 3A), LO-3 7/3 (FIG. 3B) and LO-3 9/1(FIG. 3C) on cytotoxic effect of Ketorolac in mouse intraglomerularmesangial cells (SV40 MES 13), according to an exemplary aspect.

FIG. 4A to 4D show the effects of 48 h treatment with 0.02 concentrationof LO-3 5/5 (FIG. 4A), LO-3 7/3 (FIG. 4B), LO-3 9/1 (FIG. 4C) andO-6-LCT (FIG. 4D; comparative) on cytotoxic effect of Ketorolac in mouseintraglomerular mesangial cells (SV40 MES 13), according to an exemplaryaspect.

FIG. 5 shows the cytotoxic effects of 24 h treatment with Gentamicin atvarious concentrations on mouse intraglomerular mesangial cells (SV40MES 13), according to an exemplary aspect.

FIG. 6 shows the effects of 48 h treatment with 0.005% concentration ofLO-3 9/1 on cytotoxic effect of Gentamicin in mouse intraglomerularmesangial cells (SV40 MES 13), according to an exemplary aspect.

DETAILED DESCRIPTION

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising at least one omega-3 fatty acidand at least one drug.

A further preferred embodiment is a pharmaceutical composition forparenteral administration comprising

a) an omega-3-fatty acid component selected from the group consisting ofomega-3-fatty acid triglycerides and/or omega-3-fatty acid ester, suchas omega-3 fatty acid ethyl ester; and

b) at least one drug.

An exemplary embodiment is directed to a novel injectable drug dosagecomposition comprising: a sufficient concentration of an oil derived,for example, from fish oil triglycerides containing long-chain omega-3,or n-3, fatty acids (n3-FAs); a drug having an adverse reaction profilethat is associated with damage to one or more vital organs; and a watercomponent of an emulsion designed for intravenous injection. Anexemplary composition comprises specific and concentrated bioactiven3-FAs for the purpose of addressing particular medical conditions thatmay be pharmaceutically related (U.S. application Ser. No. 12/382,196).For example, the bioactive n3-FAs are capable of providing safetreatment of iatrogenic causes of kidney disease, where drug-inducednephrotoxicities are mediated, in part, by reducing blood flow, i.e.,ischemia, by altering the vasoconstrictive effects of thromboxane A2(International Application No. PCT/US2010/000723).

As used herein, the term “oil-containing n3-FAs” pertains toconstituents such as triglycerides that are present in marine oils, aswell as constituents such as ethyl esters, which are derivatives orproducts obtained from transesterification of n3-FAs from triglyceridesto ester forms. The source of n3-FAs, however, for a given drugformulation can be, for example, wholly natural (for example,unprocessed marine oil) or semi-synthetically derived (for example,processed marine oil). The source of n3-FAs can provide sufficientamounts of bioactive EPA, DHA and/or DPA, as, for example, attached totriglycerides or ethyl ester molecules, in order to mitigate or reducethe adverse effects of a given prescribed drug on a particular vitalorgan system. The beneficial pharmacological actions attributed to thesebioactive n3-FAs include, for example, reductions in oxidative stress,inflammation, immune stimulation and ischemia arising from drug-relatedinjuries.

The provision of bioactive n3-FAs, including EPA, DHA and/or DPA, andthe downstream effects on prostaglandin metabolism, as well as thegeneration of important endogenous chemical mediators from these n3-FAprecursors (for example, resolvins and protectins), can potentially havea beneficial effect on the pathophysiological effects of many diseases.This disclosure can extend these potential benefits to apply to selecteddrugs adversely affecting vital organs of the body. For example,substituting diets that are rich in the omega-6, or n6, fatty acids(linoleic acid and arachidonic acid) with diets rich in n3-FAs (EPA, DHAand/or DPA) can significantly alter the eicosanoid profile (2-seriesprostaglandins→3-series prostaglandins; 2-series thromboxanes→3 seriesthromboxanes; 4-series leukotrienes→5-series leukotrienes). For example,prostaglandins of the 2-series derived from n6-FAs are pro-inflammatorycompared to 3-series prostaglandins derived from n3-FAs; 2-seriesthromboxanes obtained from n6-FAs are pro-vasoconstrictive/coagulantcompared to 3-series thromboxanes obtained from n3-FAs; and 4-seriesleukotrienes derived from n6-FAs produce an exaggerated immune responsecompared to 5-series leukotrienes derived from n3-FAs.

Recent findings regarding chemical mediators (for example, resolvins andprotectins) generated from n3-FAs show that the clinical benefitsregarding inflammatory processes can extend beyond the initial effect.In addition, these mediators can be actively involved in reducing theextent of oxidative stress as well as facilitating the clearance ofdebris in the affected areas and reducing the collateral damage tosurrounding tissues from an over-exuberant systemic inflammatoryresponse resulting from various physiological causes of tissue injury(for example, infection, trauma, surgery, etc.). Oxidative stress,inflammation, stimulation of the immune response and ischemia can besignificant etiological factors involved in pharmacological causes ofdrug-induced damage to vital organs, and supplying parenteral n3-FAs atthe start of medication therapy can substantially reduce these adversedrug effects, as well as reduce or eliminate accompanying morbidity andpossible mortality.

In another exemplary embodiment, the n3-FA-containing therapeutic drugvehicle can be used in combination with a prescribed drug intended forintravenous administration. Preferably, the pharmaceutical compositionof the present invention is in the form of an oil in water emulsion.

Table 1 provides a broad range of exemplary oil and water ratios inexemplary compositions, along with the corresponding intakes of thebioactive n3-FAs from a 50 mL intravenous drug admixture, as typicallyused in the clinical setting. For example, the oil to water ratio of thecomposition can be from about 0.1 to 99.9 to 20.0 to 80.0. The oil towater ratio can depend on, for example, the n3-FA content of the oilphase, the particular at least one drug and marine oil employed, and theparticular treatment.

According to another exemplary embodiment, intravenous therapies canprovide an increased bioavailability (for example, about 100% of theadministered dose) compared to other routes of administration (forexample, oral, topical, intramuscular, subcutaneous, suppository, etc.)due to alterations in absorption and/or metabolism of drugs notadministered directly into the systemic circulation. As such, theintravenous administration of the therapeutic drug vehicle can increasethe rate of incorporation of n3-FAs into plasma membranes (for example,within hours of the infusion) and greatly accelerates the onset of thebeneficial effects of n3-FAs compared to the oral, or enteral, route ofadministration, which can typically include days or weeks ofpre-treatment with n3-FAs alone before drug therapy can commence. Forexample, in a conventional process, when fish oil was used as a vehiclevia gastric lavage in an animal model of experimental nephrotoxicity, a14-day pre-treatment period was necessary to achieve sufficient plasmamembrane concentrations to mitigate kidney damage (Reference [9]). In aconventional process, in conditions where oral fish oil capsules havebeen given as therapy, for example, in patients with rheumatoidarthritis and cardiovascular disease, clinical benefits were notapparent until after several months of supplementation (Reference [31]).Thus, bioavailability, and the rapid and successful incorporation ofn3-FAs into plasma cell membranes, are crucial in achieving mitigationof adverse drug events when using n3-FA-containing injectable emulsionsas a therapeutic drug vehicle.

Another exemplary embodiment is directed to drug candidates prescribedintravenously, for which their use can be associated with significantadverse effects to vital organs, including mechanisms of toxicityinvolving oxidative stress, inflammation, immune stimulation, andischemic insult to organ tissues (Reference [10]). By virtue ofadministering such drugs intravenously, the high bioavailabilityengendered therein can increase the toxic potential of thesepharmacological agents. Vital organs of the human body can include thebrain, heart, lungs, liver and kidneys. For example, the brain is knownto be a lipid-rich environment, containing nerve cells and fibersprotected by a lipid-containing tissue known as myelin that forms aprotective sheath around neuronal structures. A risk of injury is posedby highly lipophilic drugs, such as, for example, the antiarrhythmicagent, amiodarone, a structural analog of the thyroid hormone, which canaccumulate in these lipid tissues, destroying the myelin sheath anddisrupting nerve conduction. These neurotoxic effects can causeperipheral neuropathy.

Other drugs acting in the central nervous system, such as, for example,levodopa, used in patients with Parkinson's disease, can benefit fromn3-FAs. Long-term use of levodopa has been associated with complicationsin motor function (involuntary movements) that have been linked to highconcentrations of arachidonic concentrations in the brain. The provisionof n3-FAs can compete with the n6-FA, arachidonic acid, and are thepreferred substrate for the important fatty acids in human metabolism.Thus, reducing n6-FA concentrations can be beneficial for patients withParkinson's Disease in order to reduce the adverse effects of levodopa(Reference [11]). In another example, the anticancer drug doxorubicin,an anthracycline antibiotic, can cause acute or chronic cardiotoxicityfrom oxidative stress and the production of reactive oxygen species thatinduce damage in heart tissues. In laboratory animals, pre-treatmentwith n3-FA enriched diets for at least 3 weeks has been suggested toimprove the therapeutic index of anthracycline antineoplastics(Reference [12]).

In another example, the antitumor drug, bleomycin, a basic glycopeptide,can induce an oxidative burden on lung tissues, which contain low levelsof the drug's inactivating enzyme, bleomycin hydrolase. Increasing lungtissue levels of bleomycin can cause a release of cytokines, forexample, tumor necrosis factor, and can also result in interaction withiron and molecular oxygen, which can in turn cause dangerous freeradical production. In pulmonary endothelial cell cultures exposed toamiodarone, pre-treatment with n3-FAs was shown to protect againsttoxicity (Reference [13]). In another example, the anticonvulsant,valproic acid, a branched-chain carboxylic acid, can produce hepaticsteatosis, or “fatty liver”, leading to significant liver disease. In ananimal model of necroinflammatory liver injury, pre-treatment withn3-FAs reduced oxidative damage and showed protective effects (Reference[14]). In yet other examples involving animals pre-treated with n3-FAs,several popular antibiotics, such as gentamicin (Reference [15]), andimmunosuppressive agents, such as cyclosporine (Reference [16]) wereshown to cause less kidney damage. Other drug candidates, that can causekidney damage, for example, non-steroidal anti-inflammatory agents,including ketorolac and indomethacin, as well as ionic radiocontrastagents, can also benefit from inclusion of n3-FAs in intravenousemulsions containing those drugs or agents.

In exemplary embodiments, co-administration instead of pre-treatmentwith specific n3-FAs, in high concentration, and in sufficientintravenous doses, using, for example, omega-3 acid-containing marineoils as the therapeutic drug vehicle, can greatly improve the safetyprofile of parenterally administered drugs that presently exert adverseeffects on vital organs. Pre-treatment with n3-FAs before drug therapyis not typically a reasonable option for acutely ill patients requiringdrug therapy, for whom fast action can be crucial. Hence, in such cases,supplying n3-FAs through oral or enteral administration is not typicallyviable or practical. This advantage is especially important in caseswhere such drug(s) possess a narrow therapeutic index (for example, lowratio of lethal median dose to desirable median dose). The therapeuticindex refers to the ratio of the dose required to produce a toxic effectand the dose needed to elicit the desired therapeutic response, and is arelative indication of the potency and safety of the drug. For example,the at least one drug having a narrow therapeutic index can exhibit asignificant overlap between the effective dose and the toxic dose.

An example of a drug having a narrow therapeutic index is theaminoglycoside, gentamicin, which is a broad-spectrum parenteralantibiotic against aerobic gram-negative bacteria. An exemplarytherapeutic range in plasma is between 4 to 10 μg/mL, but toxicity tothe kidneys occurs when the trough blood level (the blood level beforethe next dose) is above 2 μg/mL. Such exemplary drug has a narrowtherapeutic range and the toxicity to kidneys is associated withimpaired excretion and drug accumulation.

Another example of a drug having a narrow therapeutic index is theantifungal antibiotic amphotericin B which can have a high degree ofkidney toxicity, and occurs within the therapeutic dose range.Additional examples of drugs having a narrow therapeutic index includecyclosporine, ketorolac, cisplatin, the anthracycline cancer drugdoxorubicin. In the case doxorubicin, a cumulative dose of >550 mg/m²can be associated with cardiomyopathy. In an exemplary embodiment, theuse of n3-FAs as a therapeutic drug vehicle with these drugs having anarrow therapeutic index can mitigate the toxic responses to vitalorgans.

Table 2 depicts examples of possible drugs/categories that can beassociated with injury to vital organs. Other drugs/categories can beincluded where, for example, co-administration of concentrated n3-FAsmay accentuate the effects of the primary drug therapy. According to apreferred embodiment of the pharmaceutical composition the at least onedrug is a material that damages a vital organ when the material is notsimultaneously administered with the at least one omega-3 fatty acid,e.g. omega-3 fatty acid triglyceride and/or omega-3 fatty acid ester,such as omega-3 fatty acid ethyl ester.

The examples in Table 2 are not necessarily limiting, but rather areexamples of a broad range of possible combinations and permutations.

An exemplary embodiment can employ, for example, a dose range of fromabout 1 to about 300 mg/kg, as well as combination(s) of n3-FAs designedto accompany a prescribed drug in a proposed intravenous formulation.Table 3 provides examples of the doses (in g of n3-FAs) across theaforementioned dose range for adult patients weighing between 40 and 100kg. The entries in Table 3 can be applied to lower weights, such as forinfants and pediatric patients, where applicable. The examples in Table3 are not necessarily limiting, but are examples of a broad range ofpossible combinations and permutations.

According to an exemplary aspect, a source of n3-FAs can benaturally-occurring, semi-synthetic, synthetic, or a combinationthereof. For example, a naturally-occurring source of n3-FAs can includefish oil triglycerides. A semi-synthetically-derived source of n3-FAscan include, for example, n3-FAs attached to neutral triglycerides,ethanol as ethyl esters, or a combination thereof. The source of n3-FAscan be naturally-occurring, such as from marine oil triglycerides, butmay then be synthetically enriched. The sources of n3-FAs can be from amixture of naturally-occurring and synthetically-derived products.

For example, an oil that is derived from fish oil can be used whichcontains n3-FAs at a concentration higher than that occurring in naturalsources.

According to a preferred embodiment of the invention the pharmaceuticalcomposition comprises omega-3-fatty acid triglycerides and medium chaintriglycerides (MCT). Preferably, the pharmaceutical composition forparenteral, preferably intravenous administration, is an emulsion whichcomprises 10 to 69 wt.-% MCT, based on the total amount of the oilcomponent in the emulsion.

Preferably, the medium chain triglyceride (MCT) [triglyceride obtainedfrom esterification of glycerin with medium chain fatty acids];comprises more than 50%, more preferably more than 80% and especially atleast 95% of saturated fatty acids with 8 and 10 carbon atoms, based onthe total number of esterified fatty acids in the MCT. Further, thecomposition of the fatty acid fraction of the MCT may comprise (based onthe total number of esterified fatty acids in the MCT):

-   -   caproic acid, preferably at a maximum 2.0%; and/or    -   caprylic acid, preferably ranging from 50.0 to 80.0%; and/or    -   capric acid, preferably ranging from 20.0 to 50.0%; and/or    -   lauric acid, preferably up to a maximum of 3.0% and/or    -   myristic acid, preferably up to a maximum of 1.0%.

The oil can optionally include medium-chain fatty acids from mediumchain triglycerides (MCTs), which can be saturated medium-chain fattyacids. The oil can optionally include n6-FAs such as for example, from avegetable oil. In one embodiment, the composition such as an emulsioncan be stable, has normal metabolic clearance, and/or is well-toleratedby patients. For example, the emulsion can be an oil-in-water (o/w)emulsion.

An exemplary oil is derived from fish, and can be rich in thepolyunsaturated and bioactive omega-3 fatty acids. The oil component ofthe emulsion can contain fish oil triglycerides, for example, omega-3acid triglycerides. The fish oil triglycerides, can be present fromabout 31% to about 90%, or from about 41% to about 90%, or from about45% to about 90%, or greater than 50% to about 90%, or from about 51% toabout 90%, or from about 55% to about 90%, or from about 60% to about90%, or from about 70% to about 90%, or from about 80% to about 90%, orfrom about 40% to about 80%, or from about 50% to about 70%, or fromabout 60% to about 65%, based on the total weight of the oil componentof the emulsion. For example, by employing exemplary ranges of fish oiltriglycerides, the amount of esterified omega-3 fatty acids delivered toa human body can be increased. For example, Applicant has recognized theclinical significance of the absolute intake of omega-3 fatty acids, andhas discovered that such absolute intake of omega-3 fatty acids can beincreased by employing, for example, the exemplary ranges of fish oiltriglycerides. For example, Applicants have recognized that in at leastsome applications, for example cardiovascular health applications, theabsolute intake of omega-3 fatty acids can be a more accurate indicatorof overall efficacy than the ratio of omega-3 fatty acids to omega-6fatty acids.

They can be 20- to 22-carbon compounds and can contain 3 or more doublebonds located at the 3rd position from the methyl end of the long-chainfatty acid (LCFA) molecule. Standard notation for the various fattyacids (FAs) includes: 1) carbon number, followed by, 2) the number ofdouble bonds, and ending with 3) the position of the double bondrelative to the methyl position (or “n3” in the case of the LCFA fromfish oil). In particular, the marine oil can be highly enriched with twomajor n3-FAs, i.e., eicosapentaenoic acid, or EPA (20:5n3), anddocosahexaenoic acid, or DHA (22:5n3). The marine oil can contain lesseramounts of other n3-FAs, such as docosapentaenoic acid, or DPA (22:6n3).The fish oil component of the o/w parenteral lipid emulsion canrepresent oils from a mixture of fatty fish families, such as from thefollowing species: Engraulidae (e.g., anchovies), Carangidae (e.g.,mackerel), Clupeidae (e.g., herring), Osmeridae (e.g., smelt),Salmonidae (e.g., salmon) and Scombridge (tuna).

In the European Pharmacopeia (EP), there are two monographs (i.e., EP1352 entitled “Omega-3 Acid Triglycerides”, and, EP 1912 entitled “FishOil, Rich in Omega-3 Acids”) that pertain to fish oil that is acceptablefor use in parenteral emulsions (EP 1352, EP 1912, 2008). The monographEP 1352 substantially differs from EP 1912 in that the composition andrequirements for the bioactive n3-FAs in EP 1352 are much higher than inEP 1912 (EP 1352: EPA+DHA≧45%; total n3-FAs≧60% vs. EP 1912: EPA: ≧13%;DHA≧9%; total n3-FAs≧28%). The levels of n3-FAs in EP 1912 areconsistent with those found in nature. By comparison, in EP 1352, then3-FA concentrations are substantially higher and can be obtained by anenrichment process such as molecular distillation, whereby certainundesirable fatty acids that are present, for example, myristic acid,palmitic acid and stearic acid, are removed. In so doing, theconcentrations of all FAs present, and particularly the n3-FAs, areproportionately elevated (Reference [32]). In an exemplary embodiment,the fish oil triglycerides can include omega-3 fatty acids in an amountof at least 60%, based on the total weight of the fatty acids of thefish oil triglycerides. In an exemplary embodiment, the fish oiltriglycerides can include a total amount of EPA and DHA of at least 45%,based on the total weight of the fatty acids of the fish oiltriglycerides. For example, the fatty acids and omega-3 fatty acids(such as, for example, EPA and DHA) discussed herein refer to theconstituent parts of such acids in a fish oil triglyceride, inaccordance with EP 1352. For example, the fatty acids and omega-3 fattyacids (such as, for example, EPA and DHA) discussed above can be intheir esterified form when present in the fish oil triglycerides.

According to a preferred embodiment the pharmaceutical composition ofthe invention comprises an omega-3-fatty acid component which compriseseicosapentaenoic acid in an amount of 30% or greater, docosahexaenoicacid in an amount of 30% or less, and docosapentaenoic acid in an amountof about 40% or less, based on the weight of the total omega-3 fattyacid content.

The fish oil triglycerides can contain at least one n6-FA, for example,a plurality of n6-FAs. The at least one n6-FA can include, for example,arachidonic acid or AA (20:4n6), linoleic acid or LA (18:2n6), alphalinolenic acid or ALA (18:3n3) or a combination thereof. For example,the total content of the at least one n6-FA can be from about 0.1% toabout 1.0%, or from about 0.2% to about 0.9%, or from about 0.3% toabout 0.8%, or from about 0.4% to about 0.7%, or from about 0.5% toabout 0.6%, based on the weight of the oil component of the emulsion.

An exemplary second component of the oil component of the emulsion caninclude at least one medium chain triglyceride (MCT), for example, aplurality of MCTs. For example, the at least one MCT can be present fromabout 10% to about 69%, or from about 10% to about 40%, or from about10% to about 30%, or from about 10% to about 20%, or from about 10% toabout 15%, or from about 20% to about 60%, or from about 30% to about50%, or from about 40% to about 45%, based on the total weight of theoil component of the emulsion. For example, by employing exemplaryranges of MCT, the amount of esterified omega-3 fatty acids delivered toa human body can be increased. For example, by employing exemplary MCTranges, the amount of esterified omega-3 fatty acids delivered to ahuman body can be increased with usage of a relatively smaller amount ofMCT, while still achieving beneficial metabolic clearance andphysicochemical stability characteristics of the emulsion.

For example, the at least one MCT can include a saturated medium chainfatty acid, for example, a plurality of saturated medium chain fattyacids. In an exemplary embodiment, the MCT is a triglyceride of a fattyacid having from 6 to 12 carbon atoms. The MCT can be derived from aplant such as a vegetable, for example, a plurality of plants. The MCTcan contain caprylic acid (for example, in an amount of about 50% toabout 80% by weight of the MCT), an 8-carbon saturated FA (8:0). The MCTcan contain capric acid (for example, in an amount of about 20% to about50% by weight of the MCT), a 10-carbon saturated FA (10:0). For example,the medium-chain triglycerides can contain triglycerides of caprylicacid and capric acid, in an amount of at least 90% by weight of themedium-chain triglycerides. The description of the MCT for use in thisdisclosure can, for example, meet the requirements of EP monograph 0868,entitled “Triglycerides, Medium Chain” (Triglycerida saturate media) (EP0868, 2008).

Determination of the content of the omega-3 fatty acids can be made asdescribed in the European Pharmacopeia “Fish oil, rich in omega-3acids”. The content of n3-FAs can be from any single n3-FA, or anycombination thereof. In an exemplary embodiment, the composition cancontain EPA, DHA, DPA or a combination thereof, for example, each ofEPA, DHA and DPA. The individual dosage, for example total daily dosage,of eicosapentaenoic acid (EPA) can vary from 0 to 300 mg/kg of theformulation, for example, from 50 to 250 mg/kg, for example, from 100 to200 mg/kg, based on the body weight. The individual dosage, for exampletotal daily dosage, of docosahexaenoic acid (DHA) can vary from 0 to 300mg/kg of the formulation, for example, from 50 to 250 mg/kg, forexample, from 100 to 200 mg/kg, based on the body weight. The individualdosage, for example total daily dosage, of docosapentaenoic acid (DPA)can vary from 0 to 300 mg/kg of the formulation, for example, from 50 to250 mg/kg, for example, from 100 to 200 mg/kg, based on the body weight.For example, EPA, DHA and/or DPA can be present in amounts which areeffective to mitigate damage to at least one vital organ which wouldotherwise be caused by the at least one drug.

Preferably, the pharmaceutical composition of the invention is for usein the treatment by daily parenteral administration of the omega-3 fattyacid in an amount of about 1 to about 300 mg/kg body weight.

The individual dosage of n3-FAs can be from any single n3-FA, or anycombination thereof (for example containing EPA, DHA and DPA). In anexemplary embodiment, the individual total daily dosage of n3-FAs can beabout 1 to about 300 mg/kg, for example, about 100 to 200 mg/kg, basedon the body weight.

In another exemplary embodiment, various combinations of the bioactiven3-FAs can be present, with some therapeutic drug vehicles containingspecific percentages of selected n3-FAs. In this regard, Table 4provides a sample of possible n3-FA combinations acting as a therapeuticdrug vehicle. For example, EPA can be present in an amount from about 0%to about 100%, for example, from about 30% to about 100%, based on theweight of the total content of n3-FA. For example, DHA can be present inan amount of from about 0% to about 100%, for example, from about 0% toabout 30%, based on the weight of the total content of n3-FA. Forexample, DPA can be present in an amount of from about 0% to about 100%,for example, from about 0% to about 40%, based on the weight of thetotal content of n3-FA. The examples in Table 4 are not necessarilylimiting, but rather are examples of a broad range of possiblecombinations and permutations.

It is possible in some cases that a specific prescribed drug, within thedomain of a defined therapeutic dose, will benefit from or require aspecific dose and/or combination of n3-FAs tailored or customized to itin order to maximize the toxicity-mitigating effects of the n3-FAs.Certain prescribed drugs within a category of pharmacological agents canbenefit from a particular combination of n3-FAs, or it is possible thatsuch a vehicle can apply to a broad range of drugs and categories, inaccordance with an exemplary embodiment. Table 5 provides an example ofa therapeutic drug vehicle over several small volume infusions, and theamounts of n3-FAs a patient can receive in a 24 hour period. Theexamples in Table 5 are not necessarily limiting, but rather areexamples of a broad range of possible combinations and permutations.

The concentration of the drug in the composition and the dosage of thedrug, for example, total daily dosage, can depend on various factorssuch as, for example, the n3-FA formulation, the drug and the specificcondition being treated.

According to a preferred embodiment of the invention the pharmaceuticalcomposition comprises the drug in an amount of about 0.005 wt.-% toabout 1.5 wt.-%, based on the weight of the composition.

For example, the least one drug can be present in an amount of about0.005% to about 1.5%, for example, about 0.1% to about 0.5%, based onthe weight of the composition.

Preferably, the pharmaceutical composition is used in the treatment bydaily parenteral administration of a drug in an amount of about 0.5 toabout 50 mg/kg body weight.

The dosage of the drug can be in an amount of about 0.5 to about 50mg/kg, for example, about 10 to about 30 mg/kg, based on the weight ofthe composition. For example, the intravenous volume of a dosage of thecomposition can be about 25 to about 100 mL/dose for adults, and about 1to about 10 mL/dose for infants.

As another exemplary embodiment, the prescribed drug can be present ineither the oil fraction or the water fraction of an injectablen3-FA-containing oil-in-water emulsion, depending on the physicochemicalcharacteristics of the drug. For example, exemplary compositions andmethods can provide for the drug to be entirely present in the oilfraction, entirely present in the water fraction, or present in both theoil and water fractions. For example, this approach can be counter tocurrent practice in the pharmaceutical industry, for example, when usinginjectable oil-in-water emulsions as a pharmaceutical drug vehicle tosafely administer water-insoluble drugs via the intravenous route ofadministration (Driscoll et al, 2009).

For example, water-insoluble anesthetic/sedative agent propofol,residing in the omega-6 rich oil phase of an injectable oil-in-wateremulsion, is an example of conventional practice used in drug vehicleapplications by pharmaceutical formulators. In contrast, in an exemplaryembodiment, the omega-3 fatty acid-containing oil can function as anovel therapeutic component, as opposed to as merely a pharmaceutical(for example, carrier-only) component. Hence, its use is not limited toa particular group of drugs based on their inherent solubility andpartition coefficients with respect to a particular (for example, oil orwater) phase of the emulsion. In an exemplary embodiment, the omega-3fatty acid-containing oil can serve dual purposes, for example, as botha pharmaceutical and therapeutic drug vehicle for selectedpharmacological agents.

As another exemplary embodiment, the n3-FAs in a given formulation canaccentuate the pharmacological actions of the primary, prescribed drugand improve the therapeutic response to drug therapy. These effects canarise from additive pharmacological effects that both complement theintended actions of the primary drug and also improve and/or acceleratethe membrane altering (for example, reparative, sensitization)properties of the n3-FAs. In the first case, for example, the clinicaleffects of a diuretic such as the “high ceiling, loop diuretic”,furosemide, whose pharmacological actions involve enhanced synthesis ofvasodilatory prostaglandins that increase blood flow to the kidneys, canbe enhanced by the actions of n3-FAs that form the lessvasoconstrictive, thromboxane A3 series. This can be of particularclinical significance in critically ill patients who arefluid-overloaded and resistant to conventional diuretic therapy. Inanother example, n3-FAs can possess analgesic properties that cancomplement the actions of drug(s) used in pain management (Reference[18]). In the second case, for example, it has been suggested thatn3-FAs can improve the response to chemotherapy of various cancers byenhanced cytotoxicity of anti-cancer drugs and by reducing oxidativestress in animal and cell culture models (References [19] to [27]) andhumans (References [28] to [30]). In an exemplary embodiment, anadditional benefit of using n3-FAs as a therapeutic drug vehicle can bean improvement of clinical outcomes by accentuating the response toprimary drug therapy.

According to a preferred embodiment the pharmaceutical compositioncomprises

a) an omega-3-fatty acid component selected from the group consisting ofomega-3-fatty acid triglycerides and/or omega-3-fatty acid ethyl ester;and

b) at least one drug

for use in the treatment or prophylaxis of toxic side effects of saiddrug.

Further, the pharmaceutical composition of the invention can be used inmitigating toxicity effects of the drug. The toxicity effects arepreferably selected from the group selected from oxidative stress,inflammation, adverse immune response, ischemia and damages of vitalorgans such as kidney, brain, heart, liver and lung, more preferablyadverse drug effects selected from the group consisting of oxidativestress, inflammation, immune stimulation, ischemia of at least one vitalorgan, and a combination thereof.

In view of the complexity of the diverse actions of n3-FAs that canreduce inflammation, oxidative stress, immune modulation and ischemicinjury, and the related pharmacological actions underlying themechanisms of drug injury to vital organs, there are numerous uniqueexemplary aspects of this disclosure. Special interactions betweenn3-FAs and drugs associated with damage to vital organs can result inachieving these benefits from the onset of drug therapy by theintravenous provision of the therapeutic drug vehicle. That is, in anexemplary embodiment, the nearly complete bioavailability of theintravenous route of administration can allow rapid incorporation ofn3-FAs into plasma cell membranes to exert mitigation of the toxiceffects of selected drugs.

In an exemplary embodiment, having the option to provide n3-FAs in highconcentrations far above the levels found in natural marine sources,using semi-synthetic methods of enrichment through attachment totriglyceride or ester molecules, can further enhance their efficientincorporation into plasma cell membranes. For example, a compositiondescribed in copending U.S. application Ser. No. 12/382,196 filed onMar. 11, 2009, and International Application No. PCT/US2010/000723 filedon Mar. 11, 2010, the contents of which are incorporated by referenceherein, can be employed in the present compositions and methods. Thisexemplary advantage can be particularly beneficial, because manyintravenous drugs are provided in multiple doses over 24 hours viasmall-volume parenterals (for example, ≦100 mL). Hence, in certaincases, using wholly natural sources of fish oil, averaging approximately30% n3-FAs in the total fatty acid profile, can benefit from or requirehigher volumes of lipid emulsion per day, which may not be tolerated(for example, inducing hypertriglyceridemia). Also, the use of suchrelatively low-n3-FA-concentration natural fish oil may be unable toreasonably and safely deliver effective n3-FA doses as a therapeuticdrug vehicle at the upper limits indicated in this disclosure (forexample, up to 300 mg/kg). Use of exemplary aspects can obviate theconcerns associated with pre-treatment with n3-FAs when other routes ofadministration are applied (e.g., oral or enteral).

In a preferred embodiment the pharmaceutical composition is an emulsionwherein the emulsion comprises an oil component and a water component,the oil component comprising fish oil triglycerides in an amount ofabout 60% to about 90% based on the weight of the oil component; whereinthe fish oil triglycerides comprise omega-3 fatty acids in an amount ofat least 60%, based on the total weight of the fatty acids of the fishoil triglycerides; wherein the fish oil triglycerides comprise a totalamount of EPA and DHA of at least 45%, based on the total weight of thefatty acids of the fish oil triglycerides; and, at least onemedium-chain triglyceride, wherein a total amount of the at least onemedium-chain triglyceride is from about 10% to about 40% based on theweight of the oil component.

In an exemplary aspect, the composition employed in the method can be anemulsion comprising: an oil component and a water component, the oilcomponent comprising: fish oil triglycerides in an amount of about 60%to about 90% based on the weight of the oil component; wherein the fishoil triglycerides comprise omega-3 fatty acids in an amount of at least60%, based on the total weight of the fatty acids of the fish oiltriglycerides; wherein the fish oil triglycerides comprise a totalamount of EPA and DHA of at least 45%, based on the total weight of thefatty acids of the fish oil triglycerides; and, at least onemedium-chain triglyceride, wherein a total amount of the at least onemedium-chain triglyceride is from about 10% to about 40% based on theweight of the oil component.

According to another exemplary aspect, the composition employed in themethod can be an emulsion comprising: an oil component and a watercomponent, the oil component comprising: fish oil triglycerides in anamount of greater than 50% to about 90% based on the weight of the oilcomponent of the emulsion; wherein the fish oil triglycerides compriseomega-3 fatty acids in an amount of at least 60%, based on the totalweight of the fatty acids of the fish oil triglycerides; wherein thefish oil triglycerides comprise a total amount of EPA and DHA of atleast 45%, based on the total weight of the fatty acids of the fish oiltriglycerides; and, a medium-chain triglyceride.

According to another exemplary aspect, the composition employed in themethod can be an emulsion comprising: an oil component and a watercomponent, the oil component comprising: fish oil triglycerides in anamount of about 31% to about 90% based on the weight of the oilcomponent of the emulsion; wherein the fish oil triglycerides compriseomega-3 fatty acids in an amount of at least 60%, based on the totalweight of the fatty acids of the fish oil triglycerides; wherein thefish oil triglycerides comprise a total amount of EPA and DHA of atleast 45%, based on the total weight of the fatty acids of the fish oiltriglycerides; and, a medium-chain triglyceride; wherein the emulsion isan oil-in-water emulsion, and wherein the concentration of the oilcomponent in the emulsion is 5 g/100 mL to less than 20 g/100 mL, or theconcentration of the oil component in the emulsion is greater than 20g/100 mL to 30 g/100 mL.

In an exemplary embodiment, n3-FAs can, for example, exert theirbeneficial effects by modifying the common mechanisms of tissue injuryunderlying drug toxicity to vital organs. Fourth, by reducing the toxicpotential of drugs on vital organs, higher doses of certain drug(s) canbe given in order to address the underlying clinical problem, which canincrease the clinical efficacy of certain drug regimens in adose-dependent manner. Fifth, in selected cases, n3-FAs can improve thetherapeutic response of drugs by accentuating or complementing theirmechanisms of pharmacological actions.

The therapeutic drug vehicle can exert its toxicity-mitigating effectsof selected drugs by reducing oxidative stress, reducing inflammation,adverse immune responses, reducing ischemia, or a combination thereof.The composition of the n3-FA-containing therapeutic vehicle can betailored to a specific drug, a specific dose of a drug, several drugs inthe same therapeutic category, and/or several drugs spanning severaltherapeutic categories. The therapeutic drug vehicle can accentuate thebeneficial pharmacological effects of the drug in the formulation inaddition to mitigation of its toxicity. The therapeutic drug vehicle canaccentuate the beneficial pharmacological effects of the drug in theformulation that can reduce the amount of drug necessary with a furthermitigation in its toxicity. The therapeutic drug vehicle can improve thetherapeutic response of drug therapy and thus, clinical outcome by wayof its reparative properties. The therapeutic drug vehicle can be usedfor parenteral administration of drugs as, for example, an oil-in-waterinjectable emulsion so as to exert its beneficial effects at the onsetof drug therapy. The addition of the drug to a therapeutic drug vehicleproduced from this application can reside in either the “dispersed” or“internal” phase or in the “continuous” or “external” phase of anemulsion formulation.

In an exemplary embodiment of a method of parenterally administering thecomposition, the at least one omega-3 fatty acid and the at least onedrug are administered simultaneously. For example, such simultaneousadministration can be achieved by virtue of the at least one omega-3fatty acid and the at least one drug being present in the same emulsioncomposition. Any suitable parenteral administration can be usedincluding, for example, intravenous administration and/or intra-arterialadministration.

In an exemplary embodiment, the method does not include a pretreatmentprocess of pretreating the person with an omega-3 fatty acid prior tothe step of parenterally administering the composition. For example, thepretreatment process that is excluded according to an exemplaryembodiment can include the daily administration of an omega-3 fattyacid. For example, the pretreatment process that is excluded accordingto an exemplary embodiment is a pretreatment with an omega-3 fatty acidthat occurs 1 day or more prior to administration of the composition or,for example, 3 days or more prior to administration or, for example, 7days or more prior to administration or, for example, 14 days or moreprior to administration. For example, the pretreatment process that isexcluded according to an exemplary embodiment is a pretreatment with anomega-3 fatty acid that occurs 3 to 21 days prior to administration ofthe composition or, for example, 7 to 14 days prior to administration ofthe composition.

The pharmaceutical composition of the present invention can preferablyfurther comprise pharmaceutical acceptable ingredients, especiallyingredients which can be used for pharmaceutical compositions which areintravenously administered. According to a preferred embodiment thepharmaceutical composition comprises one or more emulsifiers, preferablyphospholipids, especially egg lecithin.

Advantageously, the pharmaceutical compositions of the present inventionadditionally comprise glycerin.

Further, the composition of the present invention may comprise sodiumoleate and/or pH-adjusting agents such as NaOH or HCl.

Further, preferably the pharmaceutical composition may comprise one ormore antioxidants, preferably α-tocopherol.

It has been found that excellent effects can be achieved forpharmaceutical compositions comprising drugs selected from the group ofantibiotics and NSAIDs, in particular wherein the drug is selected fromketorolac, a pharmaceutical acceptable salt of ketorolac and gentamicinand a pharmaceutical acceptable salt of gentamicin. A preferredembodiment of the pharmaceutical composition is an oil-in-water emulsioncomprising omega-3-fatty acid triglycerides and medium chaintriglycerides and a drug selected from ketorolac and gentamicin andpharmaceutical salts thereof.

Especially the pharmaceutical is suitable for use in mitigating thenephrotoxicity of a drug selected from ketorolac and gentamicin andpharmaceutical salts thereof.

According to a further preferred embodiment the pharmaceuticalcomposition comprises at least one drug is selected from the groupconsisting of an amphotericin, quinolone, antineoplastic agent,amiodarone, loop diuretic, azathioprine, cyclosporine, tacrolimus,indomethacin, ketorolac and a combination thereof.

Due to the excellent toxicity mitigating effect of the omega-3 fattyacid components, preferably in combination with MCT, the pharmaceuticalcomposition of the invention can comprise various classes of drugs.Particular good results can be achieved with a pharmaceuticalcomposition, wherein the at least one drug is selected from the groupconsisting of

a) Antibiotics, preferably selected from the group consisting ofaminoglycosides, amphotericin, chloramphenicol, ketoconazole,macrolides, quinolones and tetracyclines,

b) Antineoplastic Agents, preferably selected from the group consistingof alkylating agents, antimetabolites, and antimitotics platinumcoordination complexes,

c) Anti-Parkinson Agents, preferably selected from the group consistingof levodopa, pramipexole, ropinirole, rotigotine and bromocriptine,

d) Cardiovascular Agents, preferably selected from the group consistingof adenosine, amiodarone, angiotensin converting enzyme (ACE) inhibitorsand flecamide,

e) Diuretics, preferably selected from the group consisting of loopdiuretics, potassium-sparing diuretics and thiazides,

f) Immunosuppressive Agents, preferably selected from the groupconsisting of Azathioprine, Cyclosporine, Mycophenolate and Tacrolimus,

g) Psychotropics, preferably selected from the group consisting ofhaloperidol, monoamine oxidase inhibitors, phenothiazines, serotoninreuptake inhibitors and thioxanthines,

h) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), preferably selectedfrom the group consisting of acetaminophen, aspirin, ibuprofen,indomethacin and ketorolac; and

i) Pharmaceutical acceptable salts and derivatives of the drugs a) toh).

According to a specially preferred embodiment the pharmaceuticalcomposition comprises a Non-Steroidal Anti-Inflammatory Drug (NSAID)selected from the group consisting of acetaminophen, aspirin, ibuprofen,indomethacin, ketorolac as well as the pharmaceutical acceptable saltsand derivatives thereof for use in the treatment or prophylaxis of painor swelling or redness or fever or inflammation, especially for use inthe treatment or prophylaxis of severe acute post-operative pain.

Excellent results can be achieved by a pharmaceutical composition whichcomprises as the drug ketorolac or a pharmaceutical acceptable salt ofketorolac, such as ketorolac tromethamine, for use in the treatment orprophylaxis of pain or swelling or redness or inflammation, especiallyfor use in the treatment of severe acute post-operative pain. Saidpharmaceutical composition shows improved effects with respect to areduced nephrotoxicity which opens the opportunity to increase the doseto be administered.

With the pharmaceutical composition of the present invention it isgenerally possible to increase the dose of the drugs to be administeredcompared to the dose usually administered. Generally the calculation ofthe dose of a drug is a balance between the effectiveness of the drugand the possible toxic side effects. Due to the toxicity mitigatingeffect of the pharmaceutical composition of the invention the dose ofthe drugs can be increased while maintaining the toxicity effects low.Consequently, the drugs can be administered at higher doses and are moreeffective.

In an exemplary embodiment the pharmaceutical composition of theinvention can be used in the treatment by daily parenteraladministration of ketorolac tromethamine in a single dose of more than60 mg, preferably more than 75 mg; and in multiple doses of more than120 mg/day, preferably more than 150 mg/day.

According to a further preferred embodiment the pharmaceuticalcomposition comprises acetaminophen for use in the treatment orprophylaxis of pain and/or fever.

The dose of acetaminophen to be administered to a patient can besignificantly increased compared to the doses usually administered.According to a preferred embodiment the pharmaceutical composition canbe used in the treatment of patients weighing 50 kg by daily parenteraladministration of acetaminophen in a single dose of more than 1000 mg,preferably more than 1250 mg; and in multiple doses of more than 4000mg/day, preferably more than 5000 mg/day.

Especially preferably the pharmaceutical composition is for use in thetreatment of patients weighing less than 50 kg by daily parenteraladministration of acetaminophen in a single dose of more than 15 mg/kgof body weight, preferably more than 18.75 mg/kg; and in multiple dosesof more than 75 mg/kg/day, preferably more than 93.75 mg/kg/day.

According to a further preferred embodiment of the present invention thepharmaceutical composition comprises indomethacin or a pharmaceuticalacceptable salt of indomethacin, more preferably for use in thetreatment for closing a hemodynamically significant patent ductusarteriosus in premature infants weighing between 500 g and 1750 g,especially when usual medical management is ineffective. Especially forthe treatment of infants a well balanced but effective doses regime isadvisable. Therefore, in a preferred embodiment the pharmaceuticalcomposition comprises indomethacin or a pharmaceutical acceptable saltof indomethacin for use in the treatment of premature infants weighingbetween 500 g to 1750 g by parenteral administration of threeintravenous courses at 12 to 24 hour intervals with the first dose ofmore than 0.2 mg/kg, preferably more than 0.25 mg/kg and a total dose ofup to more than between 0.4 mg/kg and 0.7 mg/kg, preferably more thanbetween 0.5 mg/kg and 0.875 mg/kg.

Antibiotics and especially amionoglycoside antibiotics are especiallypreferred drugs. There is a huge demand for antibiotics which are highlyeffective, in particular antibiotics which are effective against multiresistant bacteria strains. In the prior art the administration dose andeffectiveness of antibiotics is limited due to toxic side effects.However, the preferred pharmaceutical composition of the presentinvention comprising antibiotics are more effective since a higher dosecan be administered due to the toxicity mitigating effect of thecomposition. In a preferred embodiment the pharmaceutical compositioncomprises an aminoglycoside antibiotic selected from the groupconsisting of amikacin, gentamicin, tobramycin and pharmaceuticalacceptable salts thereof, preferable for use in the treatment andprophylaxis of infections.

Preferably, the pharmaceutical composition comprises amikacin or apharmaceutical acceptable salt of amikacin, such as amikacin sulfate,for use in the treatment and prophylaxis of infections, especiallyinfections with multi-drug-resistant Gram negative bacteria such asPseudomonas aeruginosa, Acinetobacter, Enterobacter, Serratia marcescensand Providencia stuartii or for use in the treatment or prophylaxis ofnon-tubercular mycobacterial infections and tuberculosis. In anexemplary embodiment the pharmaceutical composition is for use in thetreatment by daily parenteral administration of amikacin sulfate in adose higher than 15 mg/kg body weight, preferably more than 20.25 mg/kgbody weight.

According to a further preferred embodiment the pharmaceuticalcomposition comprises as drug gentamicin or a pharmaceutical acceptablesalt of gentamicin, such as gentamicin sulfate, for use in the treatmentor prophylaxis of infections, especially systemic andurinary-tract-infection, life-threatening infections, chest-infections,bacteraemia, septicaemia, severe neonatal infections, more especiallyinfections by Escherichia coli, Klebsiella spp., Proteus spp.,Pseudomonas aeruginosa, Staphylococci, Enterobacter spp., Citrobacterspp. and Providencia spp. Especially, the pharmaceutical composition isfor use in the treatment by daily parenteral administration ofgentamicin sulfate in a single dose of more than 160 mg/kg body weight,preferably more than 224 mg/kg body weight; and in multiple doses ofmore than 5 mg/kg body weight/day, preferably more than 7 mg/kg bodyweight/day.

According to a further preferred embodiment the pharmaceuticalcomposition comprises Tobramycin or a pharmaceutical acceptable salts ofTobramycin, preferably for use in the treatment of infections,especially central nervous system infections including meningitis,septicaemia, and neonatal sepsis or gastro-intestinal infectionsincluding peritonitis or urinary tract infections such as pyelonephritisand cystitis or lower respiratory tract infections, including pneumonia,bronchopneumonia and acute bronchitis or skin, bone and soft tissueinfections including burns. Preferably, the pharmaceutical compositionis for use in the treatment by daily parenteral administration oftobramycin in a single dose higher than 5 mg/kg body weight, preferablymore than 6.75 mg/kg body weight; and in multiple doses of more than 20mg/kg body weight/day, preferably more than 27 mg/kg body weight/day.

According to a further preferred embodiment the pharmaceuticalcomposition comprises amiodarone or a pharmaceutical acceptable salt ofamiodarone, such as amiodarone hydrochloride, preferably for use in thetreatment or prophylaxis of cardiac arrhythmia or Wolff-Parkinson-Whitesyndrome, especially tachyarrhythmias selected from the group consistingof supraventricular tachycardias, nodal tachycardias, ventriculartachycardias, atrial flutter, atrial fibrillation and ventricularfibrillation. Preferably, the pharmaceutical composition is for use inthe treatment by daily parenteral administration of amiodaronehydrochloride in a dose over the first 24 hours of more than 1000 mg,preferably more than 1250 mg; and more than 720 mg as maintenanceinfusion over 24 hours, preferably more than 900 mg over 24 hours.

According to a further embodiment the pharmaceutical composition of theinvention comprises at least one drug is selected from the groupconsisting of an antineoplastic agents for use in reducing the toxicityto vital organs.

In an exemplary embodiment the pharmaceutical composition comprises atleast one drug which is selected from the group consisting ofantineoplastic agents for use in enhancing the toxicity against tumorcells.

Especially preferred is a pharmaceutical composition, wherein the atleast one drug is selected from the group consisting of anantineoplastic agents for use in simultaneously reducing the toxicity ofthe drug and enhancing its toxicity against tumor cells, preferably foruse in the treatment of cancer.

TABLE 1 Examples of various Emulsion Mixtures (Oil:Water or O:W Ratios)and Corresponding n3-FA Intakes from a 50 mL Small-Volume Drug AdmixtureDose n3-FA Content of the Oil Phase O:W Ratio 20% 40% 60% 80% 100% (g ofoil/dose) (g of n3-FA/dose) 0.1:99.9 (0.05) 0.01 0.02 0.03 0.04 0.050.5:99.5 (0.25) 0.05 0.10 0.15 0.20 0.25 1.0:99.0 (0.50) 0.10 0.20 0.300.40 0.50 5.0:95.0 (2.50) 0.50 1.00 1.50 2.00 2.50 10.0:90.0 (5.0 g)1.00 2.00 3.00 4.00 5.00 15.0:85.0 (7.5 g) 1.50 3.00 4.50 6.00 7.5020.0:80.0 (10 g) 2.00 4.00 6.00 8.00 10.00

TABLE 2 Examples of Potential Drugs/Categories Affecting Vital OrgansThat May Benefit From n3-FA Damage Mitigation Therapy 1. Antibiotics a.aminoglycosides b. amphotericin c. chloramphenicol d. ketoconazole e.macrolides f. quinolones g. tetracyclines 2. Antineoplastic Agents a.alkylating agents b. antimetabolites c. antimitotics platinumcoordination complexes 3. Anti-Parkinson Agents a. levodopa b.pramipexole c. ropinirole d. rotigotine e. bromocriptine 4.Cardiovascular Agents a. adenosine b. amiodarone c. angiotensinconverting enzyme (ACE) inhibitors d. flecainide 5. Diuretics a. loopdiuretics b. potassium-sparing diuretics c. thiazides 6.Immunosuppressive Agents a. Azathioprine b. Cyclosporine c.Mycophenolate d. Tacrolimus 7. Non-Steroidal Anti-Inflammatory Drugs(NSAIDs) a.. acetaminophen b. aspirin c. ibuprofen d. indomethacin e.ketorolac 8. Psychotropics a. haloperidol b. monoamine oxidaseinhibitors c. phenothiazines d. serotonin reuptake inhibitors e.thioxanthines

TABLE 3 Intakes of n3-FAs (g/dose) Ranging from 1 to 100 mg/kg n3-FADose Range, mg/kg Adult Patient 1 10 50 100 Weight, kg g n3-FA/bodyweight 40 0.04 0.4 2.0 4.0 50 0.05 0.5 2.5 5.0 60 0.06 0.6 3.0 6.0 700.07 0.7 3.5 7.0 80 0.08 0.8 4.0 8.0 90 0.09 0.9 4.5 9.0 100 0.10 1.05.0 10.0

TABLE 4 Sample of Potential n3-FAs and Dose Ranges (% of n3-FA OilProfile) as Therapeutic Drug Vehicles EPA DHA DPA 100 0 0 80 20 0 60 400 40 60 0 20 80 0 0 100 0 0 80 20 0 60 40 0 40 60 0 20 80 0 0 100 20 080 40 0 60 60 0 40 80 0 20 10 80 10 20 60 20 30 40 30 40 30 30 60 20 2010 10 80 20 20 60 20 40 40 30 30 40

TABLE 5 Small-Volume Parenteral Infusions and n3-FA Intakes Using a 10%Oil-in-Water Emulsion with 50% n3-FAs in the Oil Phase Infusions per Day1 2 3 4 Infusion Volume (g n3-FA)  1 mL 0.05 0.10 0.15 0.20  5 mL 0.250.50 0.75 1.00 10 mL 0.50 1.00 1.50 2.00 25 mL 1.25 2.50 3.75 5.00 50 mL2.50 5.00 7.50 10.00Cytotoxicity Study:I. Cell Lines and Culture Conditions

In vitro experiments were performed using the SV 40-transformed mousemesangial cells, [SV40 MES 13 (CRL-1927™)]. The cell line were purchasedfrom the American Type Culture Collection (ATCC-LGC Standards GmbH,Wesel, Germany). SV40 MES 13 cells were cultured in ATCC complete growthmedium: the basic medium for this cell line is a 3:1 mixture ofATCC-formulated Dulbecco's Modified Eagle's Medium [ATCC (DMEM)], andHam's F12 medium (PAA Laboratories GmbH, Colbe, Germany) with 14 mMHEPES, supplemented with 5% fetal bovine serum (FBS), 100 U/mlpenicillin, 0.1 mg/ml streptomycin. Under these culture conditions theSV40 MES 13 retained many of the differentiated characteristics ofintraglomerular mesangial cells. Cells were maintained at 37° C. in ahumidified atmosphere of 5% CO₂ and 95% air; the medium was changedevery 48 h.

II. Substances Under Test

The following stock emulsions have been prepared:

TABLE 6 Emulsion LO-3 5/5 Component Amount per 1000 ml Medium chaintriglyceride¹ 100 g Omega-3 fatty acid triglyceride² 100 g Egg lecithin 12 g Glycerin  25 g Sodium oleate  0.3 g alpha-tocopherol  0.2 g NaOHmax. 0.06 g water ad 1000 ml

TABLE 7 Emulsion LO-3 7/3 Component Amount per 1000 ml Medium chaintriglyceride¹ 60 g Omega-3 fatty acid triglyceride² 140 g  Egg lecithin12 g Glycerin 25 g Sodium oleate 0.3 g  alpha-tocopherol 0.2 g  NaOHmax. 0.06 g water ad 1000 ml

TABLE 8 Emulsion LO-3 9/1 Component Amount per 1000 ml Medium chaintriglyceride¹ 20 g Omega-3 fatty acid triglyceride² 180 g  Egg lecithin12 g Glycerin 25 g Sodium oleate 0.3 g  alpha-tocopherol 0.2 g  NaOHmax. 0.06 g water ad 1000 ml ¹Medium chain triglyceride (MCT)[triglyceride obtained from esterification of glycerine with mediumchain fatty acids; minimum 95% of saturated fatty acids with 8 and 10carbon atoms; Composition of the fatty acid fraction: caproic acid:maximum 2.0% caprylic acid: 50.0 to 80.0%, capric acid: 20.0 to 50.0%,lauic acid: maximum 3.0% and myristic acid: maximum 1.0% ²Fish oilderived Omega-3 fatty acid triglyceride in accordance with the EuropeanPharmacopeia 1352: Mixture of mono-, di- and triesters of omega-3 acidswith glycerol containing mainly triesters and obtained either byesterification of concentrated and purified omega-3 acids with glycerolor by transesterification of the omega-3 acid ethyl esters withglycerol. The origin of the omega-3 acids is the body oil from fattyfish species coming from families like Engraulidae, Carangidae,Clupeidae, Osmeridae, Salmonidae and Scombridae. The content: sum of thecontents of the omega-3 acids EPA and DHA, expressed as triglycerides:minimum 45.0% total omega-3 fatty acids, expressed as triglycerides:minimum 60.0%.

A omega-6 fatty acid long chain triglyceride containing oil is reflectedin Table 9.

TABLE 9 Emulsion O-6-LCT Component Amount per 1000 ml Soy oil 200 g  Egglecithin 12 g Glycerin 25 g Sodium oleate 0.3 g  alpha-tocopherol 0.2 g NaOH max. 0.06 g water ad 1000 ml

As shown in FIG. 2 A-C, FIG. 3 A-C, FIG. 4 A-D and FIG. 6 the stocksolutions (20%) reflected in Tables 6 to 9 have been diluted to theconcentration specified in said Figures. The concentration mentioned insaid Figures refers to the concentration of the sum of the oilcomponents, i.e. MCT and omega-3 fatty acid triglyceride and soya oilrespectively in the composition.

As an exemplary drug out of the list of NSAIDs ketorolac tromethamine istested. The following formulation has been used and tested at variousconcentrations (see FIG. 1 to FIG. 4):

Ketorolac Tromethamine Injection, USP, I.V./I.M. 30 mg/ml (Hospira,Inc., Lake Forest USA).

As an exemplary drug out of the list of antibiotics the aminoglycosidegentamicin is tested. The following formulation has been used and testedof various concentrations (see FIG. 5 and FIG. 6).

Gentamicin solution, 50 mg/ml, G1397 (Sigma-Aldrich, Saint Louis USA).

Assay Methods

In this experimental part and the Figures the drug “ketorolactromethamine” will simply be called “ketorolac”.

Determination of cytotoxic concentrations of Ketorolac or Gentamicin

2-4×10³ SV40 MES 13 cells in 100 μl medium/well were seeded in 96-wellplates (BD Falcon™, Becton Dickinson GmbH, Heidelberg, Germany). After48 h, the medium was changed and different concentrations of Ketorolac(0.1-1 mM) or Gentamicin (0.5-5 mM) were tested after 24 h treatment,cytotoxicity was measured as described below (see “determination of cellcytotoxicity”). As a control (=0% cytotoxicity), cells cultured withmedium alone, without additional treatment with Ketorolac or Gentamicinwe used.

Determination of the Cytotoxicity Mitigating Effect of the TestedEmulsions Against Cytotoxic Effects of Ketorolac or Gentamicin

4×10³ SV40 MES 13 were seeded in 100 μl medium/well in 96-well plates(BD Falcon™, Becton Dickinson GmbH, Heidelberg, Germany. After 48 h, themedium was changed and 50 μl/well medium was added. Immediately the testemulsions (Table 6 to 9) were dissolved in medium and 50 μl/well atconcentrations of 0.005%, 0.01% or 0.02% have been added to the cells.As a negative control, we used cells, which received 50 μl mediumwithout any test emulsions. After 24 h incubation with the abovementioned test emulsions, the following concentrations of Ketorolac orGentamicin were added to the MES 13 cells which were incubatedadditionally for 24 h: 0.25 mM, 0.5 mM or 1 mM or 0.5 mM, 1 mM, 2.5 mMor 5 mM respectively. The different concentrations of Ketorolac orGentamicin were added to the cells either pre-treated (24 h) with testemulsions (protective effect) or without pre-treatment (cytotoxicity ofKetorolac or Gentamicin [control]). Additional controls were performed:cells pre-treated with test emulsions, however without Ketorolac orGentamicin (control of the effect of the test emulsion) as well as cellswithout pre-treatment of the test emulsion and without Ketorolac orGentamicin (=0% cytotoxicity).

Determination of Cell Cytotoxicity

Cell cytotoxicity was assesed using PrestoBlue™ reagent (Invitrogen-LifeTechnologies GmbH, Darmstadt, Germany). PrestoBlue™ reagent is aresazurin-based solution that functions as a cell viability indicator byusing the reducing power of living cells to quantitatively measure theviability. When added to cells, the PrestoBlue™ reagent—containing anon-fluorescent, cell-permeant compound—is modified by the reducingenvironment of the viable cells, becoming highly fluorescent, which canbe detected using fluorescence or absorbance measurements (Reference[1]). PrestoBlue™ reagent is more sensible than alamarBlue, which is aredox indicator of enzyme activity widely used in whole organismscreening (Reference [2]) and is extensively used in screening test ofviability and cytotoxicity (Reference [2-6]). PrestoBlue™ was directlyadded to the cells into the culture medium at a final concentration of10%. Thereafter the plates were returned to the incubator. 30 min, 1 h,2 h, 3 h and 4 h after addition of PrestoBlue™ the optical density (OD)was measured at 570 nm and 600 nm (as reference) with a SUNRISEELISA-reader (Tecan, Salzburg, Austria). Results are expressed in % ofcytotoxicity [100-−(OD_(570/600) of samples×100/OD_(570/600) of controlwithout substances)]. The SigmaPlot software was used to carry outstatistical analyses by the unpaired Student's t test. Data are shown asmean±SEM. A p value <0.05 was considered as statistically significant.

FIGS. 1 to 6 shows the results of the Cytotoxicity measurements.

FIG. 1 demonstrates the cytotoxic effects of 24 h treatment withKetorolac at various concentrations on mouse intraglomerular mesangialcells (SV40 MES 13). Values [in % cytotoxicity of cells withouttreatment (=control, =0% cytotoxicity)] are given as mean±SEM; p,significance vs. cells without treatment (=control).

In each of the FIGS. 2A-C, 3A-C, 4A-D and 6 from left to right thecolumns have the following meaning:

-   first column: shows the cytotoxicity of the pure emulsion at the    specified concentration without the drug.-   second column: shows the cytotoxicity of the drug at the specified    concentration without the emulsion.-   third column: shows the cytotoxicity of the composition consisting    of the emulsion at the specified concentration and the drug with the    concentration as specified in the second column.-   forth column: shows the cytotoxicity of the drug of the specified    concentration without the emulsion.-   fifth column: shows the cytotoxicity of the composition consisting    of the emulsion at the specified concentration and the drug with the    concentration as specified in the forth column.-   sixth column: shows the cytotoxicity of the drug at the specified    concentration without the emulsion.-   seventh column: shows the cytotoxicity of the composition consisting    of the emulsion at the specified concentration and the drug with the    concentration as specified in the sixth column.

FIGS. 2A to 2C show the effects of 48 h treatment with 0.005%concentrations of LO-3 5/5 (FIG. 2A), LO-3 7/3 (FIG. 2B) and LO-3 9/1(FIG. 2C) on cytotoxic effect of Ketorolac in mouse intraglomerularmesangial cells (SV40 MES 13). Values [in % cytotoxicity of cellswithout treatment (=control, =0% cytotoxicity)] are given as mean±SEM;p, significance vs. Ketorolac treatment; n=4 independent experiments,using 4-6 wells per treatment and experiment.

FIGS. 3A to 3C show the effects of 48 h treatment with 0.01concentration of LO-3 5/5 (FIG. 3A), LO-3 7/3 (FIG. 3B) and LO-3 9/1(FIG. 3C) on cytotoxic effect of Ketorolac in mouse intraglomerularmesangial cells (SV40 MES 13). Values [in % cytotoxicity of cellswithout treatment (=control, =0% cytotoxicity)] are given as mean±SEM;p, significance vs. Ketorolac treatment; n=4 independent experiments,using 4-6 wells per treatment and experiment.

FIG. 4A to 4D show the effects of 48 h treatment with 0.02 concentrationof LO-3 5/5 (FIG. 4A), LO-3 7/3 (FIG. 4B), LO-3 9/1 (FIG. 4C) andO-6-LCT (FIG. 4D; comparative) on cytotoxic effect of Ketorolac in mouseintraglomerular mesangial cells (SV40 MES 13). Values [in cytotoxicityof cells without treatment (=control, =0% cytotoxicity)] are given asmean±SEM; p, significance vs. Ketorolac treatment; n=4 independentexperiments, using 4-6 wells per treatment and experiment.

FIG. 5 demonstrates the cytotoxic effects of 24 h treatment withGentamicin at various concentrations on mouse intraglomerular mesangialcells (SV40 MES 13). Values [in % cytotoxicity of cells withouttreatment (=control, =0% cytotoxicity)] are given as mean±SEM; p,significance vs. cells without treatment (=control).

FIG. 6 shows the effects of 48 h treatment with 0.005% concentration ofLO-3 9/1 on cytotoxic effect of Gentamicin in mouse intraglomerularmesangial cells (SV40 MES 13). Values [in % cytotoxicity of cellswithout treatment (=control, =0% cytotoxicity)] are given as mean±SEM;p, significance vs. Gentamicin treatment; n=4 independent experiments,using 4-6 wells per treatment and experiment.

While various embodiments are described herein, it will be appreciatedthat variations, modifications and other changes in form and detail maybe made without departing from the spirit and scope of the disclosure.Such variations and modifications are to be considered within thepurview and scope of the disclosure as defined by the appended claims.

REFERENCE LIST

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The invention claimed is:
 1. A pharmaceutical composition for parenteraladministration comprising at least one omega-3 fatty acid, medium chaintriglycerides (MCT), and at least one drug, wherein the composition isin the form of an oil-in-water emulsion, wherein the emulsion comprises10 to 69 wt.-% MCT, based on the total amount of the oil component inthe emulsion.
 2. A pharmaceutical composition for parenteraladministration comprising a) an omega-3-fatty acid component selectedfrom the group consisting of omega-3-fatty acid triglycerides,omega-3-fatty acid ester, and a combination thereof; b) medium chaintriglycerides (MCI); and c) at least one drug, wherein the compositionis in the form of an oil-in-water emulsion, wherein the emulsioncomprises 10 to 69 wt.-% MCT, based on the total amount of the oilcomponent in the emulsion.
 3. The pharmaceutical composition accordingto claim 1 wherein the at least one omega-3 fatty acid and the at leastone drug are administered simultaneously.
 4. The pharmaceuticalcomposition according to claim 1 comprising a) an omega-3-fatty acidcomponent selected from the group consisting of omega-3-fatty acidtriglycerides, omega-3-fatty acid ethyl ester and a combination thereof;and b) at least one drug for use in the treatment or prophylaxis oftoxic side effects of said drug.
 5. The pharmaceutical compositionaccording to claim 1 for use in mitigating toxicity effects of said drugand wherein the toxicity effects are selected from the group consistingof oxidative stress, inflammation, adverse immune response, ischemia anddamages of vital organs.
 6. The pharmaceutical composition according toclaim 1 wherein the composition comprises omega-3-fatty acidtriglycerides and medium chain triglycerides (MCT).
 7. Thepharmaceutical composition according to claim 1, wherein the emulsioncomprises an oil component and a water component, the oil componentcomprising fish oil triglycerides in an amount of about 60% to about 90%based on the weight of the oil component; wherein the fish oiltriglycerides comprise omega-3 fatty acids in an amount of at least 60%,based on the total weight of the fatty acids of the fish oiltriglycerides; wherein the fish oil triglycerides comprise a totalamount of EPA and DHA of at least 45%, based on the total weight of thefatty acids of the fish oil triglycerides; and, at least onemedium-chain triglyceride, wherein a total amount of the at least onemedium-chain triglyceride is from about 10% to about 40% based on theweight of the oil component.
 8. The pharmaceutical composition accordingto claim 1 wherein the omega-3-fatty acid component compriseseicosapentaenoic acid in an amount of 30% or greater, docosahexaenoicacid in an amount of 30% or less, and docosapentaenoic acid in an amountof about 40% or less, based on the weight of the total omega-3 fattyacid content.
 9. The pharmaceutical composition according to claim 1 foruse in the treatment by daily parenteral administration of said omega-3fatty acid in an amount of about 1 to about 300 mg/kg.
 10. Thepharmaceutical composition according to claim 1, wherein the at leastone drug is a material that damages a vital organ when the material isnot simultaneously administered with the at least one omega-3 fattyacid.
 11. The pharmaceutical composition according to claim 1, whereinthe at least one drug is present in an amount of about 0.005% to about1.5%, based on the weight of the composition.
 12. The pharmaceuticalcomposition according to claim 1, for use in the treatment by dailyparenteral administration of said drug in an amount of about 0.5 toabout 50 mg/kg body weight.
 13. The pharmaceutical composition accordingto claim 1 comprising an oil in water emulsion comprising omega-3-fattyacid triglycerides and medium chain triglycerides and a drug selectedfrom the group consisting of ketorolac and gentamicin.
 14. Thepharmaceutical composition of claim 1 for use in mitigating thenephrotoxicity of a drug selected from the group consisting of ketorolacand gentamicin.
 15. The pharmaceutical composition according to claim 1,wherein the at least one drug is selected from the group consisting ofan amphotericin, quinolone, antineoplastic agent, amiodarone, loopdiuretic, azathioprine, cyclosporine, tacrolimus, indomethacin,ketorolac and a combination thereof.
 16. The pharmaceutical compositionaccording to claim 1, wherein the at least one drug is selected from thegroup consisting of a) Antibiotics selected from the group consisting ofaminoglycosides, amphotericin, chloramphenicol, ketoconazole,macrolides, quinolones and tetracyclines, b) Antineoplastic Agentsselected from the group consisting of alkylating agents,antimetabolites, and antimitotics platinum coordination complexes, c)Anti-Parkinson Agents selected from the group consisting of levodopa,pramipexole, ropinirole, rotigotine and bromocriptine, d) CardiovascularAgents selected from the group consisting of adenosine, amiodarone,angiotensin converting enzyme (ACE) inhibitors and flecainide, e)Diuretics selected from the group consisting of loop diuretics,potassium-sparing diuretics and thiazides, f) Immunosuppressive Agentsselected from the group consisting of Azathioprine, cyclosporine,Mycophenolate and Tacrolimus, g) Psychotropics selected from the groupconsisting of haloperidol, monoamine oxidase inhibitors, phenothiazines,serotonin reuptake inhibitors and thioxanthines, h) Non-SteroidalAnti-Inflammatory Drugs (NSAIDs) selected from the group consisting ofacetaminophen, aspirin, ibuprofen, indomethacin and ketorolac; and i)Pharmaceutical acceptable salts and derivatives of the drugs a) to h).17. The pharmaceutical composition according to claim 1, wherein the atleast one drug is a Non-Steroidal Anti-Inflammatory Drug selected fromthe group consisting of acetaminophen, aspirin, ibuprofen, indomethacin,ketorolac, and pharmaceutical acceptable salts and derivatives thereoffor use in the treatment or prophylaxis of pain or swelling or rednessor fever or inflammation.
 18. The pharmaceutical composition accordingto claim 17, wherein the at least one drug is ketorolac or apharmaceutical acceptable salt of ketorolac, for use in the treatment orprophylaxis of pain or swelling or redness or inflammation.
 19. Thepharmaceutical composition according to claim 18 for use in thetreatment by daily parenteral administration of ketorolac tromethaminein a single dose of more than 60 mg.
 20. The pharmaceutical compositionaccording to claim 2, wherein the omega-3-fatty acid component includesan omega-3 fatty acid ethyl ester.
 21. The pharmaceutical compositionaccording to claim 18, wherein the at least one drug is ketorolactromethamine.
 22. The pharmaceutical composition according to claim 1,wherein the at least one drug is present in both the oil component andthe aqueous component of the emulsion.
 23. The pharmaceuticalcomposition according to claim 2, wherein the at least one drug ispresent in both the oil component and the aqueous component of theemulsion.
 24. The pharmaceutical composition according to claim 1,wherein the oil component of the emulsion consists of fish oiltriglycerides and MCT, wherein the fish oil triglycerides includeomega-3 fatty acids in an amount of at least 60%, based on the totalweight of the fatty acids of the fish oil triglycerides, and wherein thefish oil triglycerides include a total amount of EPA and DHA of at least45%, based on the total weight of the fatty acids of the fish oiltriglycerides.
 25. The pharmaceutical composition according to claim 2,wherein the oil component of the emulsion consists of fish oiltriglycerides and MCT, wherein the fish oil triglycerides includeomega-3 fatty acids in an amount of at least 60%, based on the totalweight of the fatty acids of the fish oil triglycerides, and wherein thefish oil triglycerides include a total amount of EPA and DHA of at least45%, based on the total weight of the fatty acids of the fish oiltriglycerides.
 26. A method of administering a drug within apharmaceutical composition to a person in need thereof, comprisingparenterally administering an effective amount of the pharmaceuticalcomposition of claim 1 to said person.
 27. The method according to claim26, wherein the at least one omega-3 fatty acid is obtained from amarine oil, and wherein the at least one omega-3 fatty acid is in anaturally occurring form.
 28. The method according to claim 26, whereinthe at least one omega-3 fatty acid is obtained from a marine oil, andwherein the at least one omega-3 fatty acid is in a non-naturallyoccurring form.
 29. The method according to claim 26, wherein the atleast one omega-3 fatty acid is obtained from a marine oil, and whereinthe at least one omega-3 fatty acid is attached to neutraltriglycerides, ethanol as ethyl esters or a combination thereof.
 30. Themethod according to claim 26, wherein the at least one omega-3 fattyacid comprises eicosapentaenoic acid, docosahexaenoic acid anddocosapentaenoic acid.
 31. The method according to claim 30, wherein theeicosapentaenoic acid is present in an amount of 30% or greater, thedocosahexaenoic acid is present in an amount of 30% or less, and thedocosapentaenoic acid is present in an amount of about 40% or less,based on the weight of the total omega-3 fatty acid content.
 32. Themethod according to claim 30, wherein a total daily dosage of the atleast one omega-3 fatty acid is about 1 to about 300 mg/kg, based on theweight of the total omega-3 fatty acid content.
 33. The method accordingto claim 26, wherein the composition is in the form of an emulsioncomprising an oil phase and a water phase, wherein the at least oneomega-3 fatty acid is present in the oil phase and the at least one drugis present in the oil and/or water phase(s).
 34. The method according toclaim 26, wherein the method does not include a pretreatment process ofpretreating the person with an omega-3 fatty acid source prior toparenterally administering the composition.
 35. The method according toclaim 26, wherein the at least one drug is a material that damages avital organ when the material is not simultaneously administered withthe at least one omega-3 fatty acid.
 36. The method according to claim26, wherein the at least one drug is selected from the group consistingof an amphotericin, quinolone, antineoplastic agent, amiodarone, loopdiuretic, azathioprine, cyclosporine, tacrolimus, indomethacin,ketorolac and a combination thereof.
 37. The method according to claim26, wherein the at least one omega-3 fatty acid is present in an amountthat is effective to reduce or eliminate at least one adverse drugeffect selected from the group consisting of oxidative stress,inflammation, immune stimulation, ischemia of at least one vital organ,and a combination thereof.
 38. The method according to claim 26, whereinthe at least one drug is present in an amount of about 0.005% to about1.5%, based on the weight of the composition.
 39. The method accordingto claim 26, wherein a dosage of the drug is in an amount of about 0.5to about 50 mg/kg, based on the weight of the composition.
 40. Themethod according to claim 26, wherein the parenteral administrationcomprises intravenous administration.